The overall goal of this Program Project Grant (P01) is to define the key interactions between multiple intracellular pathogens and infected host cells. Over the last 10 years, many of the host innate immune pathways involved in sensing microbial infection have been identified. The receptors controlling the activation of these pathways include the Toll-like receptors (TLRs) and a growing family of cytosolic receptors including Nods, Naips, Nalps, and multiple cytosolic nucleic acid sensors. Importantly, the contribution of each of these pathways during a microbial infection will differ based on the composition, lifestyle, and virulence mechanisms of that microbe. Core B of this P01 will maintain a colony of mouse strains with deficiencies in components of innate immunity or other genetic modifications useful for the study of innate immunity. Core B also supports an ENU-based forward genetic screen to identify new genes involved in host defense during L. monocytogenes, L. pneumophila, and M. tuberculosis infection. Mice and macrophages derived from these mice will be distributed to each of the projects within the P01. All mouse strains have been or will be backcrossed onto the C57B1/6 genetic background to equivalent degrees. Core B will reduce overall mouse costs due to economies of scale. In addition, each P01 project will benefit from using cells and mice with fewer genetic and experimental variations.